Die Rolle neuer „pro-resolving” Lipidmediatoren bei entzündlichen Lungenerkrankungen

 

 Permissions and Reprints

Zusammenfassung

Erkrankungen mit unkontrollierter pulmonaler Entzündung stellen eine wesentliche medizinische Herausforderung, aber auch ökonomische Belastung für unsere Gesellschaft dar. Derzeit existieren keine Therapeutika, die diese Art der pathologischen Entzündungen gezielt kontrollieren. Kürzlich wurde eine neue Gruppe von antientzündlichen und proresolutionären Lipidmediatoren entdeckt: Lipoxine, Resolvine, Protektine und Maresine. Diese Lipidmediatoren werden enzymatisch aus den mehrfach ungesättigten Fettsäuren (PUFAs) Arachidonsäure (AA), Docosahexaensäure (DHA) und Eicosapentaensäure (EPA) gebildet, welche seit langem bekannte positive Wirkungen auf diverse Krankheitsverläufe haben können. Diese neuen Lipidmediatoren zeigen in vitro und in vivo in murinen pulmonalen Entzündungsmodellen vielversprechende antiinflammatorische Wirkungen und könnten eine entscheidende Rolle in der Therapie von vielen entzündlichen Lungenerkrankungen, wie z. B. des Asthmas bronchiale, der cystischen Fibrose (CF) und des akuten Lungenversagens spielen.

Abstract

Uncontrolled inflammation of the lung contributes to the major medical and economic burden on healthcare, and the need for therapeutics to dampen pathological inflammation is largely unmet. Recently, a new genus of anti-inflammatory/ pro-resolving lipid mediators has been identified: Lipoxins, resolvins, protectins and maresins. These compounds are enzymatically derived from the polyunsaturated fatty acids (PUFAs) arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) that have long been known to have beneficial health properties. These mediators have potent anti-inflammatory effects in vitro and in vivo in murine models of lung inflammation. Therefore, this group of compounds carries considerable therapeutic potential for the treatment of many inflammatory lung diseases including asthma, cystic fibrosis and acute lung injury.

Literatur

• 1 Nathan C, Ding A. Nonresolving inflammation.  Cell. 2010;  140 871-882
  CrossrefPubMedGoogle Scholar
• 2 Serhan C N, Chiang N, Van Dyke T E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.  Nat Rev Immunol. 2008;  8 349-361
  CrossrefPubMedGoogle Scholar
• 3 Serhan C N, Savill J. Resolution of inflammation: the beginning programs the end.  Nat Immunol. 2005;  6 1191-1197
  CrossrefPubMedGoogle Scholar
• 4 Karp C L, Flick L M, Park K W. et al . Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway.  Nat Immunol. 2004;  5 388-392
  CrossrefPubMedGoogle Scholar
• 5 Celik G E, Erkekol F O, Misirligil Z, Melli M. Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity.  Clin Exp Allergy. 2007;  37 1494-1501
  PubMedGoogle Scholar
• 6 Levy B D, Bonnans C, Silverman E S. et al . Diminished lipoxin biosynthesis in severe asthma.  Am J Respir Crit Care Med. 2005;  172 824-830
  CrossrefPubMedGoogle Scholar
• 7 Tahan F, Saraymen R, Gumus H. The role of lipoxin A4 in exercise-induced bronchoconstriction in asthma.  J Asthma. 2008;  45 161-164
  CrossrefPubMedGoogle Scholar
• 8 Serhan C N, Hamberg M, Samuelsson B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes.  Proc Natl Acad Sci U S A. 1984;  81 5335-5339
  CrossrefPubMedGoogle Scholar
• 9 Serhan C N, Hamberg M, Samuelsson B. Trihydroxytetraenes: a novel series of compounds formed from arachidonic acid in human leukocytes.  Biochem Biophys Res Commun. 1984;  118 943-949
  CrossrefPubMedGoogle Scholar
• 10 Serhan C N. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways.  Annu Rev Immunol. 2007;  25 101-137
  CrossrefPubMedGoogle Scholar
• 11 Fiore S, Serhan C N. Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils.  J Exp Med. 1990;  172 1451-1457
  CrossrefPubMedGoogle Scholar
• 12 Levy B D, Romano M, Chapman H A. et al . Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins.  J Clin Invest. 1993;  92 1572-1579
  CrossrefPubMedGoogle Scholar
• 13 Claria J, Serhan C N. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions.  Proc Natl Acad Sci U S A. 1995;  92 9475-9479
  CrossrefPubMedGoogle Scholar
• 14 Claria J, Lee M H, Serhan C N. Aspirin-triggered lipoxins (15-epi-LX) are generated by the human lung adenocarcinoma cell line (A549)-neutrophil interactions and are potent inhibitors of cell proliferation.  Mol Med. 1996;  2 583-596
  PubMedGoogle Scholar
• 15 Planaguma A, Pfeffer M A, Rubin G. et al . Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4.  Mucosal Immunol. 2010;  3 270-279
  CrossrefPubMedGoogle Scholar
• 16 Serhan C N, Fiore S, Brezinski D A, Lynch S. Lipoxin A4 metabolism by differentiated HL-60 cells and human monocytes: conversion to novel 15-oxo and dihydro products.  Biochemistry. 1993;  32 6313-6319
  CrossrefPubMedGoogle Scholar
• 17 Serhan C N, Maddox J F, Petasis N A. et al . Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils.  Biochemistry. 1995;  34 14 609-14 615
  PubMedGoogle Scholar
• 18 Burr G O, Burr M M. Nutrition classics from The Journal of Biological Chemistry 82: 345 – 67, 1929. A new deficiency disease produced by the rigid exclusion of fat from the diet.  Nutr Rev. 1973;  31 248-249
  PubMedGoogle Scholar
• 19 Marchioli R, Barzi F, Bomba E. et al . Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione.  Circulation. 2002;  105 1897-1903
  CrossrefPubMedGoogle Scholar
• 20 Mickleborough T D, Lindley M R, Ionescu A A, Fly A D. Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma.  Chest. 2006;  129 39-49
  CrossrefPubMedGoogle Scholar
• 21 Freedman S D, Blanco P G, Zaman M M. et al . Association of cystic fibrosis with abnormalities in fatty acid metabolism.  N Engl J Med. 2004;  350 560-569
  CrossrefPubMedGoogle Scholar
• 22 Serhan C N, Clish C B, Brannon J. et al . Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing.  J Exp Med. 2000;  192 1197-1204
  CrossrefPubMedGoogle Scholar
• 23 Serhan C N, Hong S, Gronert K. et al . Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.  J Exp Med. 2002;  196 1025-1037
  CrossrefPubMedGoogle Scholar
• 24 Wittamer V, Franssen J D, Vulcano M. et al . Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids.  J Exp Med. 2003;  198 977-985
  CrossrefPubMedGoogle Scholar
• 25 Arita M, Bianchini F, Aliberti J. et al . Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1.  J Exp Med. 2005;  201 713-722
  CrossrefPubMedGoogle Scholar
• 26 Ohira T, Arita M, Omori K. et al . Resolvin E1 receptor activation signals phosphorylation and phagocytosis.  J Biol Chem. 2010;  285 3451-3461
  CrossrefPubMedGoogle Scholar
• 27 Arita M, Ohira T, Sun Y P. et al . Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation.  J Immunol. 2007;  178 3912-3917
  PubMedGoogle Scholar
• 28 Hong S, Gronert K, Devchand P R. et al . Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation.  J Biol Chem. 2003;  278 14 677-14 687
  PubMedGoogle Scholar
• 29 Serhan C N, Gotlinger K, Hong S. et al . Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes.  J Immunol. 2006;  176 1848-1859
  PubMedGoogle Scholar
• 30 Duffield J S, Hong S, Vaidya V S. et al . Resolvin D series and protectin D1 mitigate acute kidney injury.  J Immunol. 2006;  177 5902-5911
  PubMedGoogle Scholar
• 31 Sun Y P, Oh S F, Uddin J. et al . Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation.  J Biol Chem. 2007;  282 9323-9334
  CrossrefPubMedGoogle Scholar
• 32 Mattoscio D, Evangelista V, De Cristofaro R. et al . Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response.  FASEB J. 2010;  24 3970-3980
  CrossrefPubMedGoogle Scholar
• 33 Spite M, Norling L V, Summers L. et al . Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis.  Nature. 2009;  461 1287-1291
  CrossrefPubMedGoogle Scholar
• 34 Krishnamoorthy S, Recchiuti A, Chiang N. et al . Resolvin D1 binds human phagocytes with evidence for proresolving receptors.  Proc Natl Acad Sci USA. 2010;  107 1660-1665
  CrossrefPubMedGoogle Scholar
• 35 Marcheselli V L, Hong S, Lukiw W J. et al . Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression.  J Biol Chem. 2003;  278 43 807-43 817
  PubMedGoogle Scholar
• 36 Lukiw W J, Cui J G, Marcheselli V L. et al . A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease.  J Clin Invest. 2005;  115 2774-2783
  CrossrefPubMedGoogle Scholar
• 37 Gonzalez-Periz A, Planaguma A, Gronert K. et al . Docosahexaenoic acid (DHA) blunts liver injury by conversion to protective lipid mediators: protectin D1 and 17S-hydroxy-DHA.  FASEB J. 2006;  20 2537-2539
  CrossrefPubMedGoogle Scholar
• 38 Marcheselli V L, Mukherjee P K, Arita M. et al . Neuroprotectin D1/protectin D1 stereoselective and specific binding with human retinal pigment epithelial cells and neutrophils.  Prostaglandins Leukot Essent Fatty Acids. 2010;  82 27-34
  CrossrefPubMedGoogle Scholar
• 39 Serhan C N, Yang R, Martinod K. et al . Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions.  J Exp Med. 2009;  206 15-23
  CrossrefPubMedGoogle Scholar
• 40 Soehnlein O, Lindbom L. Phagocyte partnership during the onset and resolution of inflammation.  Nat Rev Immunol. 2010;  10 427-439
  CrossrefPubMedGoogle Scholar
• 41 Holgate S T. The epidemic of allergy and asthma.  Nature. 1999;  402 B2-B4
  CrossrefPubMedGoogle Scholar
• 42 Martinez Molina D, Wetterholm A, Kohl A. et al . Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase.  Nature. 2007;  448 613-616
  CrossrefPubMedGoogle Scholar
• 43 Busse W W, Lemanske Jr R F. Asthma.  N Engl J Med. 2001;  344 350-362
  CrossrefPubMedGoogle Scholar
• 44 Vachier I, Bonnans C, Chavis C. et al . Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound.  J Allergy Clin Immunol. 2005;  115 55-60
  CrossrefPubMedGoogle Scholar
• 45 Sanak M, Levy B D, Clish C B. et al . Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics.  Eur Respir J. 2000;  16 44-49
  CrossrefPubMedGoogle Scholar
• 46 Bonnans C, Vachier I, Chavis C. et al . Lipoxins are potential endogenous antiinflammatory mediators in asthma.  Am J Respir Crit Care Med. 2002;  165 1531-1535
  CrossrefPubMedGoogle Scholar
• 47 Planaguma A, Kazani S, Marigowda G. et al . Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma.  Am J Respir Crit Care Med. 2008;  178 574-582
  CrossrefPubMedGoogle Scholar
• 48 Levy B D, Clish C B, Schmidt B. et al . Lipid mediator class switching during acute inflammation: signals in resolution.  Nat Immunol. 2001;  2 612-619
  CrossrefPubMedGoogle Scholar
• 49 Haworth O, Cernadas M, Yang R. et al . Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation.  Nat Immunol. 2008;  9 873-879
  CrossrefPubMedGoogle Scholar
• 50 Lee T H, Crea A E, Gant V. et al . Identification of lipoxin A4 and its relationship to the sulfidopeptide leukotrienes C4, D4, and E4 in the bronchoalveolar lavage fluids obtained from patients with selected pulmonary diseases.  Am Rev Respir Dis. 1990;  141 1453-1458
  PubMedGoogle Scholar
• 51 Levy B D, De Sanctis G T, Devchand P R. et al . Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A(4).  Nat Med. 2002;  8 1018-1023
  CrossrefPubMedGoogle Scholar
• 52 Christie P E, Spur B W, Lee T H. The effects of lipoxin A4 on airway responses in asthmatic subjects.  Am Rev Respir Dis. 1992;  145 1281-1284
  PubMedGoogle Scholar
• 53 Riordan J R, Rommens J M, Kerem B. et al . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.  Science. 1989;  245 1066-1073
  CrossrefPubMedGoogle Scholar
• 54 Anderson M P, Gregory R J, Thompson S. et al . Demonstration that CFTR is a chloride channel by alteration of its anion selectivity.  Science. 1991;  253 202-205
  CrossrefPubMedGoogle Scholar
• 55 Brennan S. Innate immune activation and cystic fibrosis.  Paediatr Respir Rev. 2008;  9 271-279; quiz 279 – 280
  CrossrefPubMedGoogle Scholar
• 56 Eickmeier O, Huebner M, Herrmann E. et al . Sputum biomarker profiles in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) and association between pulmonary function.  Cytokine. 2010;  50 152-157
  CrossrefPubMedGoogle Scholar
• 57 Khan T Z, Wagener J S, Bost T. et al . Early pulmonary inflammation in infants with cystic fibrosis.  Am J Respir Crit Care Med. 1995;  151 1075-1082
  PubMedGoogle Scholar
• 58 Bonfield T L, Panuska J R, Konstan M W. et al . Inflammatory cytokines in cystic fibrosis lungs.  Am J Respir Crit Care Med. 1995;  152 2111-2118
  PubMedGoogle Scholar
• 59 Konstan M W, Walenga R W, Hilliard K A, Hilliard J B. Leukotriene B4 markedly elevated in the epithelial lining fluid of patients with cystic fibrosis.  Am Rev Respir Dis. 1993;  148 896-901
  CrossrefPubMedGoogle Scholar
• 60 Hartl D, Latzin P, Hordijk P. et al . Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease.  Nat Med. 2007;  13 1423-1430
  CrossrefPubMedGoogle Scholar
• 61 Kuo P T, Huang N N, Bassett D R. The fatty acid composition of the serum chylomicrons and adipose tissue of children with cystic fibrosis of the pancreas.  J Pediatr. 1962;  60 394-403
  PubMedGoogle Scholar
• 62 Barnes P J. Immunology of asthma and chronic obstructive pulmonary disease.  Nat Rev Immunol. 2008;  8 183-192
  CrossrefPubMedGoogle Scholar
• 63 Martins V, Valenca S S, Farias-Filho F A. et al . ATLa, an aspirin-triggered lipoxin A4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis.  J Immunol. 2009;  182 5374-5381
  CrossrefPubMedGoogle Scholar
• 64 Bernard G R, Artigas A, Brigham K L. et al . The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.  Am J Respir Crit Care Med. 1994;  149 818-824
  CrossrefPubMedGoogle Scholar
• 65 Wheeler A P, Bernard G R. Acute lung injury and the acute respiratory distress syndrome: a clinical review.  Lancet. 2007;  369 1553-1564
  CrossrefPubMedGoogle Scholar
• 66 Ware L B, Matthay M A. The acute respiratory distress syndrome.  N Engl J Med. 2000;  342 1334-1349
  CrossrefPubMedGoogle Scholar
• 67 Mizgerd J P. Acute lower respiratory tract infection.  N Engl J Med. 2008;  358 716-727
  CrossrefPubMedGoogle Scholar
• 68 Fukunaga K, Kohli P, Bonnans C. et al . Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury.  J Immunol. 2005;  174 5033-5039
  PubMedGoogle Scholar
• 69 Gilroy D W, Colville-Nash P R, Willis D. et al . Inducible cyclooxygenase may have anti-inflammatory properties.  Nat Med. 1999;  5 698-701
  CrossrefPubMedGoogle Scholar
• 70 Schwartz J, Weiss S T. The relationship of dietary fish intake to level of pulmonary function in the first National Health and Nutrition Survey (NHANES I).  Eur Respir J. 1994;  7 1821-1824
  CrossrefPubMedGoogle Scholar
• 71 Schubert R, Kitz R, Beermann C. et al . Effect of n-3 polyunsaturated fatty acids in asthma after low-dose allergen challenge.  Int Arch Allergy Immunol. 2009;  148 321-329
  CrossrefPubMedGoogle Scholar
• 72 Bettelli E, Oukka M, Kuchroo V K. T(H)-17 cells in the circle of immunity and autoimmunity.  Nat Immunol. 2007;  8 345-350
  CrossrefPubMedGoogle Scholar
• 73 Molet S, Hamid Q, Davoine F. et al . IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines.  J Allergy Clin Immunol. 2001;  108 430-438
  CrossrefPubMedGoogle Scholar
• 74 Park H, Li Z, Yang X O. et al . A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.  Nat Immunol. 2005;  6 1133-1141
  CrossrefPubMedGoogle Scholar
• 75 Cheung P F, Wong C K, Lam C W. Molecular mechanisms of cytokine and chemokine release from eosinophils activated by IL-17A, IL-17F, and IL-23: implication for Th17 lymphocytes-mediated allergic inflammation.  J Immunol. 2008;  180 5625-5635
  PubMedGoogle Scholar
• 76 Gadek J E, DeMichele S J, Karlstad M D. et al . Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group.  Crit Care Med. 1999;  27 1409-1420
  CrossrefPubMedGoogle Scholar
• 77 Pacht E R, DeMichele S J, Nelson J L. et al . Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants reduces alveolar inflammatory mediators and protein influx in patients with acute respiratory distress syndrome.  Crit Care Med. 2003;  31 491-500
  CrossrefPubMedGoogle Scholar
• 78 Pontes-Arruda A, Aragao A M, Albuquerque J D. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock.  Crit Care Med. 2006;  34 2325-2333
  CrossrefPubMedGoogle Scholar
• 79 Singer P, Theilla M, Fisher H. et al . Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury.  Crit Care Med. 2006;  34 1033-1038
  CrossrefPubMedGoogle Scholar
• 80 Kang J X, Wang J, Wu L, Kang Z B. Transgenic mice: fat-1 mice convert n-6 to n-3 fatty acids.  Nature. 2004;  427 504
  CrossrefPubMedGoogle Scholar
• 81 Mayer K, Kiessling A, Ott J. et al . Acute lung injury is reduced in fat-1 mice endogenously synthesizing n-3 fatty acids.  Am J Respir Crit Care Med. 2009;  179 474-483
  CrossrefPubMedGoogle Scholar
• 82 Seki H, Fukunaga K, Arita M. et al . The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury.  J Immunol. 2010;  184 836-843
  CrossrefPubMedGoogle Scholar
• 83 Meduri G U, Kohler G, Headley S. et al . Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome.  Chest. 1995;  108 1303-1314
  CrossrefPubMedGoogle Scholar
• 84 Levy B D, Kohli P, Gotlinger K. et al . Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness.  J Immunol. 2007;  178 496-502
  PubMedGoogle Scholar
• 85 Colgan S P, Serhan C N, Parkos C A. et al . Lipoxin A4 modulates transmigration of human neutrophils across intestinal epithelial monolayers.  J Clin Invest. 1993;  92 75-82
  CrossrefPubMedGoogle Scholar
• 86 Papayianni A, Serhan C N, Brady H R. Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells.  J Immunol. 1996;  156 2264-2272
  PubMedGoogle Scholar
• 87 Levy B D, Fokin V V, Clark J M. et al . Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a ’stop’ signaling switch for aspirin-triggered lipoxin A4.  Faseb J. 1999;  13 903-911
  PubMedGoogle Scholar
• 88 Soyombo O, Spur B W, Lee T H. Effects of lipoxin A4 on chemotaxis and degranulation of human eosinophils stimulated by platelet-activating factor and N-formyl-L-methionyl-L-leucyl-L-phenylalanine.  Allergy. 1994;  49 230-234
  CrossrefPubMedGoogle Scholar
• 89 Bandeira-Melo C, Bozza P T, Diaz B L. et al . Cutting edge: lipoxin (LX) A4 and aspirin-triggered 15-epi-LXA4 block allergen-induced eosinophil trafficking.  J Immunol. 2000;  164 2267-2271
  PubMedGoogle Scholar
• 90 Ariel A, Chiang N, Arita M. et al . Aspirin-triggered lipoxin A4 and B4 analogs block extracellular signal-regulated kinase-dependent TNF-alpha secretion from human T cells.  J Immunol. 2003;  170 6266-6272
  PubMedGoogle Scholar
• 91 Ramstedt U, Serhan C N, Nicolaou K C. et al . Lipoxin A-induced inhibition of human natural killer cell cytotoxicity: studies on stereospecificity of inhibition and mode of action.  J Immunol. 1987;  138 266-270
  PubMedGoogle Scholar
• 92 Godson C, Mitchell S, Harvey K. et al . Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages.  J Immunol. 2000;  164 1663-1667
  PubMedGoogle Scholar
• 93 Aliberti J, Hieny S, Reis e Sousa C. et al . Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity.  Nat Immunol. 2002;  3 76-82
  CrossrefPubMedGoogle Scholar
• 94 Gewirtz A T, McCormick B, Neish A S. et al . Pathogen-induced chemokine secretion from model intestinal epithelium is inhibited by lipoxin A4 analogs.  J Clin Invest. 1998;  101 1860-1869
  CrossrefPubMedGoogle Scholar
• 95 Brezinski M E, Gimbrone Jr. M A, Nicolaou K C, Serhan C N. Lipoxins stimulate prostacyclin generation by human endothelial cells.  FEBS Lett. 1989;  245 167-172
  CrossrefPubMedGoogle Scholar
• 96 Bonnans C, Fukunaga K, Levy M A, Levy B D. Lipoxin A(4) regulates bronchial epithelial cell responses to acid injury.  Am J Pathol. 2006;  168 1064-1072
  CrossrefPubMedGoogle Scholar
• 97 Campbell E L, Louis N A, Tomassetti S E. et al . Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution.  Faseb J. 2007;  21 3162-3170
  CrossrefPubMedGoogle Scholar
• 98 Schwab J M, Chiang N, Arita M, Serhan C N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes.  Nature. 2007;  447 869-874
  CrossrefPubMedGoogle Scholar
• 99 Haworth O, Cernadas M, Yang R. et al . Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A(4) to promote the resolution of allergic airway inflammation.  Nat Immunol. 2008;  9 873-879
  CrossrefPubMedGoogle Scholar
• 100 Ariel A, Fredman G, Sun Y P. et al . Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression.  Nat Immunol. 2006;  7 1209-1216
  CrossrefPubMedGoogle Scholar
• 101 Ariel A, Li P L, Wang W. et al . The docosatriene protectin D1 is produced by TH2 skewing and promotes human T cell apoptosis via lipid raft clustering.  J Biol Chem. 2005;  280 43 079-43 086
  PubMedGoogle Scholar
• 102 Bannenberg G L, Chiang N, Ariel A. et al . Molecular circuits of resolution: formation and actions of resolvins and protectins.  J Immunol. 2005;  174 4345-4355
  CrossrefPubMedGoogle Scholar
• 103 Mukherjee P K, Marcheselli V L, Serhan C N, Bazan N G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.  Proc Natl Acad Sci U S A. 2004;  101 8491-8496
  CrossrefPubMedGoogle Scholar
• 104 Fiorucci S, Wallace J L, Mencarelli A. et al . A beta-oxidation-resistant lipoxin A4 analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction.  Proc Natl Acad Sci U S A. 2004;  101 15 736-15 741
  PubMedGoogle Scholar
• 105 Chiang N, Gronert K, Clish C B. et al . Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion.  J Clin Invest. 1999;  104 309-316
  CrossrefPubMedGoogle Scholar
• 106 Fierro I M, Kutok J L, Serhan C N. Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15R-lipoxin A(4) and lipoxin A(4).  J Pharmacol Exp Ther. 2002;  300 385-392
  CrossrefPubMedGoogle Scholar
• 107 Svensson C I, Zattoni M, Serhan C N. Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing.  J Exp Med. 2007;  204 245-252
  CrossrefPubMedGoogle Scholar
• 108 Serhan C N, Jain A, Marleau S. et al . Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators.  J Immunol. 2003;  171 6856-6865
  PubMedGoogle Scholar
• 109 Gronert K, Maheshwari N, Khan N. et al . A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense.  J Biol Chem. 2005;  280 15 267-15 278
  PubMedGoogle Scholar
• 110 Hasturk H, Kantarci A, Ohira T. et al . RvE1 protects from local inflammation and osteoclast-mediated bone destruction in periodontitis.  Faseb J. 2006;  20 401-403
  PubMedGoogle Scholar
• 111 Hasturk H, Kantarci A, Goguet-Surmenian E. et al . Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo.  J Immunol. 2007;  179 7021-7029
  PubMedGoogle Scholar
• 112 Connor K M, SanGiovanni J P, Lofqvist C. et al . Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis.  Nat Med. 2007;  13 868-873
  CrossrefPubMedGoogle Scholar
• 113 Arita M, Yoshida M, Hong S. et al . Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis.  Proc Natl Acad Sci U S A. 2005;  102 7671-7676
  CrossrefPubMedGoogle Scholar
• 114 Weylandt K H, Kang J X, Wiedenmann B, Baumgart D C. Lipoxins and resolvins in inflammatory bowel disease.  Inflamm Bowel Dis. 2007;  13 797-799
  CrossrefPubMedGoogle Scholar

Dr. med. Olaf Eickmeier

Zentrum für Kinder- und Jugendmedizin
Allergologie, Pneumologie und Mukoviszidose
Klinikum der Johann Wolfgang Goethe-Universität

Theodor-Stern-Kai 7
60590 Frankfurt/Main

Email: olaf.eickmeier@kgu.de